I. Adrenergic Nervous System: Overview Uses adrenaline (epinephrine) and noradrenaline (norepinephrine) as neurotransmitters OH OH HO NHMe HO NH2 HO HO E pinephrine (A drenaline) N orepinephrine (N oradrenaline) 1. Nerve Transmission Peripheral nervous system Skeletal muscle CNS (Somatic) Ach (N) CNS (Autonomic) Synapse Ach (N) NA Sympathetic Adrenaline Parasympathetic Ach (N) Adrenal medulla AUTONOMIC Synapse Ach (N) Ach (M) Smooth muscle Cardiac muscle http://www.sickkids.on.ca/childphysiology/cpwp/Urinary/kidney.swf http://en.wikipedia.org/wiki/Adrenal_gland Fight or Flight? вЂў The fight-or-flight response, also called the acute stress response, was first described by Walter Cannon in 1929. His theory states that animals react to threats with a general discharge of the sympathetic nervous system, priming the animal for fighting or fleeing. This response was later recognized as the first stage of a general adaptation syndrome that regulates stress responses among vertebrates and other organisms. вЂў Normally, when a person is in a serene, unstimulated state, the "firing" of neurons in the locus ceruleus is minimal. A novel stimulus (which could include a perception of danger or an environmental stressor signal such as elevated sound levels or over-illumination), once perceived, is relayed from the sensory cortex of the brain through the thalamus to the brain stem. That route of signaling increases the rate of noradrenergic activity in the locus ceruleus, and the person becomes alert and attentive to the environment. Similarly, an abundance of catecholamines at neuroreceptor sites facilitates reliance on spontaneous or intuitive behaviors often related to combat or escape.If a stimulus is perceived as a threat, a more intense and prolonged discharge of the locus ceruleus activates the sympathetic division of the autonomic nervous system (Thase & Howland, 1995). This activation is associated with specific physiological actions in the system, both directly and indirectly through the release of epinephrine (adrenaline) and to a lesser extent norepinephrine from the medulla of the adrenal glands. The release is triggered by acetylcholine released from preganglionic sympathetic nerves. The other major player in the acute stress response is the hypothalamic-pituitary-adrenal axis. Fight or Flight Response: вЂў These catecholamine hormones facilitate immediate physical reactions associated with a preparation for violent muscular action. (Gleitman, et al, 2004). These include the following: вЂў пЅҐAcceleration of heart and lung actionпЅҐInhibition of stomach and intestinal action пЅҐConstriction of blood vessels in many parts of the body пЅҐLiberation of nutrients for muscular action пЅҐDilation of blood vessels for muscles пЅҐInhibition of tear glands and salivation пЅҐDilation of pupil пЅҐRelaxation of bladder пЅҐInhibition of erection вЂў вЂў вЂў вЂў вЂў вЂў вЂў Adrenergic Receptors вЂў In 1948, adrenergic receptors were subdivided into alpha and beta by Ahlquist. The distinction was based on sensitivities of different organs to catecholamines of closely related structure. Regulation of the functions of different organs depends to a greater or lesser extent on alpha or beta receptors. вЂў Alpha receptors are located postsynaptically at sympathetic neuroeffector junctions of many organs. In general, alpha receptors mediate excitation or increased activity of the effector cells. Vascular smooth muscle is an important site of alpha receptors. SNS activity maintains vascular tone, and thus blood pressure, by maintaining a tone of neurotransmitter on vascular alpha receptors. вЂў Beta receptors are also located postsynaptically at sympathetic neuroeffector junctions of many organs. In general, beta receptors mediate relaxation or decreased activity of the effector cells. Thus, blood vessels dilate and uterine smooth muscle relaxes in response to activation of beta receptors. Heart muscle is an important exception to this rule. Activation of beta adrenoceptors in heart increases the automaticity and contractility of all parts of the heart. Types of пЃЎ-adrenergic receptor п‚• пЃЎ-adrenergic receptors are adrenergic receptors that respond to norepinephrine and to such blocking agents as phenoxybenzamine. вЂў They are subdivided into two types: п‚• пЃЎ1, found in smooth muscle, heart, and liver, with effects including vasoconstriction, intestinal relaxation, uterine contraction and pupillary dilation, п‚• пЃЎ2, found in platelets, vascular smooth muscle, nerve termini, and pancreatic islets, with effects including platelet aggregation, vasoconstriction, and inhibition of norepinephrine release and of insulin secretion. пЃў-receptor types п‚• пЃў-adrenergic receptors respond particularly to epinephrine and to such blocking agents as propranolol. вЂў There are three known types of beta receptor, designated ОІ1, ОІ2 and ОІ3. вЂў ОІ1-Adrenergic receptors are located mainly in the heart. вЂў ОІ2-Adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. вЂў ОІ3-receptors are located in fat cells. What do the receptors do? Activation of пЃЎ receptors leads to smooth muscle contraction Activation of пЃў2 receptors leads to smooth muscle relaxation Activation of пЃў1 receptors leads to smooth muscle contraction (especially in heart) Clinical Utility of drugs which affect the adrenergic nervous system: a. Agonists of the пЃў2 receptors are used in the treatment of asthma (relaxation of the smooth muscles of the bronchi) b. Antagonists of the пЃў1 receptors are used in the treatment of hypertension and angina (slow heart and reduce force of contraction) c. Antagonists of the пЃЎ1 receptors are known to cause lowering of the blood pressure (relaxation of smooth muscle and dilation of the blood vessels) Definitions вЂў Sympathetic and parasympathetic divisions typically function in opposition to each other. But this opposition is better termed complementary in nature rather than antagonistic. For an analogy, one may think of the sympathetic division as the accelerator and the parasympathetic division as the brake. вЂў The sympathetic division typically functions in actions requiring quick responses. вЂў The parasympathetic division functions with actions that do not require immediate reaction. вЂў Consider sympathetic as "fight or flight" and parasympathetic as "rest and digest". OH OH HO NHMe HO NH2 HO HO E pinephrine (A drenaline) N orepinephrine (N oradrenaline) вЂўEpinephrine (INN) (IPA: [ЛЊЙ›pЙЄЛ€nЙ›frЙ™n]) or adrenaline (European Pharmacopoeia and BAN) (IPA: [Й™Л€drЙ›nЙ™lЙ™n]), sometimes spelled "epinephrin" or "adrenalin" respectively, is a hormone. It is a catecholamine, a sympathomimetic monoamine derived from the amino acids phenylalanine and tyrosine. вЂўThe Latin roots ad-+renes and the Greek roots epi-+nephros both literally mean "on/to the kidney" (referring to the adrenal gland, which secretes epinephrine). Epinephrine is sometimes shortened to epi in medical jargon. вЂўEpinephrine is now also used in EpiPens and Twinjects. EpiPens are long narrow autoinjectors that administer epinephrine, Twinjects are similar but contain two doses of epinephrine. Though both EpiPen and Twinject are trademark names, common usage of the terms are drifting toward the generic context of any epinephrine autoinjector. http://www.maxanim.com/biochemistry/Epinephrine/Epin ephrine.htm EpiPen EpiPen is a registered trademark for the most commonly used autoinjector of epinephrine (aka adrenaline), used in medicine to treat anaphylactic shock. http://www.epipen.com/howtouse_high.aspx Anaphylaxis Anaphylaxis is a severe and rapid multi-system allergic reaction. The term comes from the Greek words ana (against) and phyllus (protection). Anaphylaxis occurs when a person is exposed to a trigger substance, called an allergen, to which they have already become sensitized. Minute amounts of allergens may cause a life-threatening anaphylactic reaction. Anaphylaxis may occur after ingestion, inhalation, skin contact or injection of an allergen. The most severe type of anaphylaxisвЂ”anaphylactic shockвЂ”will usually lead to death in minutes if left untreated. Most common presentation is sudden cardiovascular collapse (88% of reported cases of severe anaphylaxis). Anaphylactic shock Anaphylactic shock, the most serious of allergic reactions, is a life-threatening medical emergency because of rapid constriction of the airway, often within minutes of onset. Calling for help immediately is important, as brain and organ damage rapidly occurs if the patient cannot breathe. Anaphylactic shock requires immediate advanced medical care; but other first aid measures include rescue breathing (part of CPR) and administration of epinephrine (adrenaline). Rescue breathing may be hindered by the constricted airways but is essential if the victim stops breathing on their own. If the patient has previously been diagnosed with anaphylaxis, they may be carrying an EpiPen (or similar device) for immediate administration of epinephrine (adrenaline) by a layperson to help keep the airway open. Use of an EpiPen or similar device will only provide temporary and limited relief of symptoms, so emergency medical services must still be contacted. Repetitive administration of epinephrine can cause tachycardia (rapid heartbeat) and occasionally ventricular tachycardia with heart rates potentially reaching 240 beats per minute, which can also be fatal. Extra doses of epinephrine can sometimes cause cardiac arrest. This is why some protocols advise intramuscular injection of only 0.3вЂ“0.5mL of a 1:1,000 dilution. The epinephrine will prevent worsening of the airway constriction, stimulate the heart to continue beating, and may be life-saving. Ephinephrine can be injected directly into the heart to stimulate it after it as stopped beating due to drowning, suffocation, shock, electrocution, and anesthesia. The epinephrine dramatically restores the heart beat. In cases of shock, norepinephrine has been used to restore and maintain sufficient blood pressure and ensure adequate blood flow to vital organs. When local anesthetics are used to reduce or eliminate pain in a specific area, epinephrine is frequently used in conjunction with these agents to constrict the blood vessels at the area and prevent drug diffusion from that area 1. Nerve Transmission Peripheral nervous system Skeletal muscle CNS (Somatic) Ach (N) CNS (Autonomic) Synapse Ach (N) NA Sympathetic Adrenaline Parasympathetic Ach (N) Adrenal medulla AUTONOMIC Synapse Ach (N) Ach (M) Smooth muscle Cardiac muscle п‚· Norad r enaline r eleased at junction smooth muscle and card iac muscle of nerve with п‚· Adrenaline relea s ed by a drenal medulla and circulates through blood supply (stimulates heart, for exampl e ) п‚· These two neurot neurotransmitter r ansmitters act opposite a ce tylc h oline the Endocrine Glands (general) вЂў http://pennhealth.com/health_info/anima tionplayer/endocrine_glands.html Adrenal Gland вЂў http://health.howstuffworks.com/adam200053.htm вЂў http://en.wikipedia.org/wiki/Image:Illu_a drenal_gland.jpg вЂў http://www.answers.com/topic/adrenalgland Biosynthesis of norepinephrine and epinephrine NH2 C O 2H HO HO T y ro sin e hyd ro x y lase NH2 C O 2H HO L -T y ro sine HO D o pa D ecarb o xy lase NH2 HO D o pam ine L ev od op a OH OH D o p am in e пЃў -h yd rox y lase HO HO NH2 N -m eth y l transferase (in A d ren al m ed ulla) HO N orep in ep hrin e (N oradren aline) NHMe HO E pinep hrine (A d renalin e) Metabolism involves two key enzymes: MAO and COMT OH HO OH NH2 M on oam ine O xidase HO (M A O ) OH NH HO H 2O HO O HO HO U n stable Im in e N orepinephrine (N o radrenaline) OH OH HO O OH HO C atech ol-O -M eth yl T ransferase C H 3O O OH (C O M T ) HO The design of a drug to treat asthma вЂў Asthma is a chronic disease of the respiratory system in which the airway occasionally constricts, becomes inflamed, and is lined with excessive amounts of mucus, often in response to one or more triggers. These acute episodes may be triggered by such things as exposure to an environmental stimulant (or allergen), cold air, exercise or exertion, or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold. This airway narrowing causes symptoms such as wheezing, shortness of breath, chest tightness, and coughing, which respond to bronchodilators. Between episodes, most patients feel fine.The disorder is a chronic or recurring inflammatory condition in which the airway develops increased responsiveness to various stimuli, characterized by bronchial hyper-responsiveness, inflammation, increased mucus production, and intermittent airway obstruction. The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and environmental changes.Public attention in the developed world has recently focused on asthma because of its rapidly increasing prevalence, affecting up to one in four urban children. What is asthma? вЂў http://www.1on1health.com/web/info/asthma/english/asthmaanimation/AnimationPage/LookListenLearnType=1 вЂў http://www.whatsasthma.org/flash/hasthmav.html вЂў http://www.healthcentral.com/animation/408/46.html What is COPD? http://allergy.health.ivillage.com/animations/show_animations. cfm?cmbtopics=210 http://www.exploriaproductions.com/movies/IVAX_320x240.mov COPD вЂў Chronic obstructive pulmonary disease (COPD), also known as chronic obstructive airway disease (COAD), is a group of diseases characterised by limitation of airflow in the airway that is not fully reversible. COPD is the umbrella term for chronic bronchitis and/or emphysema. It is most often due to tobacco smoking  but can be due to other airborne irritants such as coal dust or solvents. Chronic Bronchitis Chronic bronchitis is defined in clinical terms as a cough with sputum production on most days for 3 months of a year, for 2 consecutive years. Chronic bronchitis is hallmarked by the increased number (hyperplasia) and increased size (hypertrophy) of the mucus-secreting (goblet) cells of the airway. This, along with enlargement of the mucous gland, results in an increase in production of mucus which contributes to the airway obstruction. Microscopically there is infiltration of the airway walls with inflammatory cells, particularly neutrophils. Inflammation is followed by scarring and remodelling that thickens the walls resulting in narrowing of the small airway. Further progression leads to an abnormal change (metaplasia) in the nature of the tissue along with further thickening and scarring (fibrosis) of the lower airway. The consequence of these changes is a limitation of airflow.  Emphysema Main article: Emphysema Emphysema is defined histologically as the enlargement of the air spaces distal to the terminal bronchioles, with destruction of their walls. The enlarged air sacs (alveoli) of the lungs reduces the surface area available for the movement of gases during respiration. This can cause breathlessness in severe cases. The exact mechanism for the development of emphysema is not understood, although it it known to be linked with smoking and age. Historically, what therapeutic agents have been used? вЂў Ephedrine, as part of the Chinese medicine Ma Huang, has been used in the treatment of respiratory diseases for over 5000 years вЂў Ephedrine is now known to act indirectly, by releasing endogenous catecholamines, resulting in bronchodilation вЂў In 1900, Solis-Cohen showed that orally administered adrenal extract was beneficial in asthma. Historic вЂў Initially, subcutaneous injections of epinephrine were used, followed by a nebulized epinephrine solution. вЂў Epinephrine is one of the most potent vasopressor (i.e. causes constriction of the blood vessels and corresponding rise in blood pressure) drugs known. вЂў Epinephrine affects respiration primarily by relaxing the bronchial muscle. вЂў Epinephrine is rapidly metabolized by COMT, primarily in the liver. Can we make an asthma drug with less side effects, and longer lasting? вЂў Clues: вЂў It is known that the пЃў2 receptor is the target for relaxation of bronchial smooth muscle. вЂў Epinephrine has approx. equal affinity for both пЃЎ and пЃў receptors вЂў However norepinephrine has greater affinity for the пЃЎ receptors вЂў This indicates that placing an alkyl group on the nitrogen leads to an increase in selectivity for the пЃў-receptors. OH OH HO NHMe HO NH2 HO HO E pinephrine (A drenaline) Equal selectivity for Both пЃЎпЂ and пЃў-receptors N orepinephrine (N oradrenaline) Greater selectivity for пЃЎпЂreceptors Perhaps, still greater selectivity for пЃў-receptors could be Generated by appending larger alkyl substituent on nitrogen An improvement! OH HO H N HO Iso pren aline вЂў Isoprenaline was synthesized by German chemists in the 1940вЂ™s вЂў It had less cardiovacular side effects than adrenaline вЂў Became the most widely used inhaled treatment for asthma for the next 20 years. Further improvements needed вЂў Needed an agent which was longer lasting, more resistant to COMT вЂў Needed an agent which was more selective for the пЃў2 receptors in the lung and less selective for the пЃў1 receptors of heart. Arrives Salbutamol OH HOCH2 H N HO S alb u tam o l вЂў Tert-butyl group renders salbutamol more selective for пЃў2 вЂў Hydroxymethyl group (in place of OH) renders salbutamol resistant to COMT вЂў Remains the most widely used anti-asthma drug in the world Salbutamol вЂў Salbutamol (INN) or albuterol (USAN) is a short-acting ОІ2adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and COPD.Salbutamol sulphate is usually given by the inhaled route for direct effect on bronchial smooth muscle. This is usually achieved through a metered dose inhaler (MDI), nebuliser or other proprietary delivery devices (e.g. Rotahaler or Autohaler). In these forms of delivery, the effect of Salbutamol can take place within 5 to 20 minutes of dosing. Salbutamol can also be given orally or intravenously. However, some asthmatics may not respond to these medications as they will not have the required DNA base sequence in a specific gene.Salbutamol became available in the United Kingdom in 1969 and in the United States in 1980 under the trade name Ventolin. OH HOCH2 H N O HO S alm eterol Salmeterol is a long-acting beta2-adrenergic receptor agonist drug that is currently prescribed for the treatment of asthma and chronic obstructive pulmonary disease COPD. It is currently available in both dry-powder inhalers (DPIs) and pressurised metered dose inhalers (pMDIs). It is a long acting beta-adrenoceptor agonist (LABA), usually only prescribed for severe persistent asthma following previous treatment with a short-acting beta agonist such as salbutamol and is prescribed concurrently with a corticosteroid, such as beclometasone. The primary noticeable difference of salmeterol to salbutamol is that the duration of action lasts approximately 12 hours in comparison with 4пѕђ6 hours of salbutamol. BRONCHODILATORS, ADRENERGIC (Inhalation)* In the U.S.Adrenalin Chloride 3 Airet 1 Alupent 8 Arm-a-Med Isoetharine 6 Arm-a-Med Metaproterenol 8 Asthmahaler Mist 3 AsthmaNefrin 3 Beta-2 6 Brethaire 12 Bronkaid Mist 3 Bronkaid Suspension Mist 3 Bronkometer 6 Bronkosol 6 Dey-Lute Isoetharine 6 Dey-Lute Metaproterenol 8 Foradil 5 Isuprel 7 Isuprel Mistometer 7 Maxair 9 Maxair Autohaler 9 Medihaler-Iso 7 microNefrin 3 Nephron 3 Primatene Mist 3 Proventil 1 Proventil HFA 1 S-2 3 Serevent Diskus 11 Vaponefrin 3 Ventolin 1 Ventolin HFA 1 Ventolin Nebules 1 Ventolin Rotacaps 1tolin Rotacaps 1 In CanadaAlupent 8 Apo-Salvent 1 Berotec 4 Bricanyl Turbuhaler 12 Bronkaid Mistometer 3 Foradil 5 Gen-Salbutamol Sterinebs P.F. 1 Isuprel 7 Isuprel Mistometer 7 Maxair 9 Novo-Salmol 1 Oxeze Turbuhaler 5 Pro-Air 10 Serevent 11 Serevent Diskhaler 11 Serevent Diskus 11 Vaponefrin 3 Ventodisk 1 Ventolin 1 Ventolin Nebules P.F. 1 Ventolin Rotacaps 1tolin Rotacaps 1 This information applies to the following medicines: 1.Albuterol (al-BYOO-ter-ole)вЂЎВ§ 2.Bitolterol (bye-TOLE-ter-ole)*вЂ 3.Epinephrine (ep-i-NEF-rin)вЂЎ 4.Fenoterol (fen-OH-ter-ole)* 5.Formoterol (for-MOH-ter-ol))вЂЎВ§ 6.Isoetharine (eye-soe-ETH-a-reen)вЂ вЂЎ 7.Isoproterenol (eye-soe-proe-TER-e-nole)вЂЎ 8.Metaproterenol (met-a-proe-TER-e-nole)вЂЎ 9.Pirbuterol (peer-BYOO-ter-ole) 10.Procaterol (proe-KAY-ter-ole)* 11.Salmeterol# (sal-ME-te-role)* 12.Terbutaline (ter-BYOO-ta-leen) Treatment of COPD вЂў BronchodilatorsThere are three types of bronchodilators used clinically: ОІ2-agonists, anticholinergics and methylxanthines.These drugs relax the smooth muscles of the airway allowing for improved airflow. Many patients feel less breathless after taking bronchodilators. CombiventВ® Salbutamol / Ipratropium bromide Presentation Inhaler 100mcg / 20 mcg per inhalation Combivent metered dose inhaler has an opaque shaft with a grey mouthpiece and cap. The canister contains a creamy-white homogenous suspension of micronised substances in a chlorofluorohydrocarbon propellant mixture filled in an aluminium canister with a metering valve. Each metered dose contains salbutamol 100 mcg (equivalent to 120 mcg salbutamol sulphate), and ipratropium bromide 20 mcg (equivalent to 21 mcg of ipratropium bromide monohydrate). RespulesВ® 2.5mg / 500mcg in 2.5ml Combivent 2.5ml Respule contains an isotonic, clear, preservative-free solution for inhalation of 2.5mg salbutamol (equivalent to 3.01mg salbutamol sulphate) and 500 mcg ipratropium bromide anhydrous (equivalent to 520 mcg ipratropium bromide monohydrate) Uses Actions Combivent contains two active bronchodilating substances, salbutamol sulphate and ipratropium bromide. Salbutamol sulphate is a beta2-adrenergic agent which acts on airway smooth muscle resulting in relaxation. Salbutamol relaxes all smooth muscle from the trachea to the terminal bronchioles and protects against all bronchoconstrictor challenges. Ipratropium bromide is a quaternary ammonium compound with anticholinergic properties. In preclinical studies, it appears to inhibit vagally mediated reflexes by antagonising the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increase of intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) caused by interaction of acetylcholine with muscarinic receptors on bronchial smooth muscle. The bronchodilation following inhalation of ipratropium bromide is primarily local and site specific to the lung and not systemic in nature. Combivent provides the simultaneous release of ipratropium bromide and salbutamol allowing the synergistic efficacy on the muscarinic and beta2-adrenergic receptors in the airways to cause bronchodilation which is superior to that provided by each single agent and with no potentiation of adverse Cholinergic Antagonists (Muscarinic receptor) Br C H ( C H 3) 2 H 3C N H C H 2 OH O CH C O Ipratropium (bronchodilator & anti-asthmatic) Adrenergic Receptors in the CNS вЂў http://www.brainexplorer.org/video/index .shtml пЃЎ-Blockers вЂў Alpha blockers (also called alpha-adrenergic blocking agents) constitute a variety of drugs which block О±1adrenergic receptors in arteries and smooth muscles. вЂў These drugs may be used to treat:пЅҐbenign prostatic hyperplasia (BPH)пЅҐhigh blood pressure (hypertension). This is not typically the drug of choice unless the patient also has BPH.пЅҐsymptoms of non inflammatory chronic pelvic pain syndrome, a type of prostatitis. As a side effect they may reduce blood pressure and result in lightheadedness. Benign Prostatic Hyperplasia вЂў http://www.muschealth.com/gs/Animatio nList.aspx#anim4 вЂў http://health.howstuffworks.com/adam200003.htm Treatment of benign prostatic hyperplasia (BPH) Medications Alpha blockers (О±1-adrenergic receptor antagonists) (such as doxazosin, prazosin, alfuzosin and tamsulosin) and certain antiandrogens such as the 5О±-reductase inhibitors (finasteride and dutasteride) are used, often together, in suppressing the symptoms. Alpha-blockers relax smooth muscle in the prostate and bladder neck decreasing the degree of blockage of urine flow. Alpha-blockers may cause ejaculation back into the bladder (retrograde ejaculation). This is not harmful. There is also extensive evidence of the efficacy of Serenoa repens (saw palmetto) fruit extracts in alleviating mild-to-moderate BPH symptoms. A systematic review of evidence found comparable efficacy to finasteride. (Wilt et al., 2002) Other herbal medicines that have solid research support in systematic reviews include beta-sitosterol from Hypoxis rooperi (African star grass) and Prunus africanum (pygeum) bark, while there is less substantial support for the efficacy of Cucurbita pepo (pumpkin) seed and Urtica dioica (stinging nettle) root. (Wilt et al., 2000) At least one double-blind trial has also supported the efficacy of rye flower pollen. (Buck, et al., 1990) Sildenafil shows some symptomatic relief, suggesting a possible common etiology with erectile disfunction. (Brown 2005)o Examples of commercial пЃЎ-blockers O O O N N N O N N N OMe OMe O N N P razo sin (M in ipress, H y p o vase) OMe D o x azosin (C ard u ra, P fizer) NH2 OMe NH2 N O N H N H 2N S O 2 O N H CH3 OH H 3C O Cl P hen ox y b en zam in e P hen to lam in e T am su lo sin (F lo m ax, A stellas P harm a) O C 2H 5 пЃў-Blockers вЂў Beta blockers (sometimes written as ОІ-blockers) are a class of drugs used for various indications, but particularly for the management of cardiac arrhythmias and cardioprotection after myocardial infarction. Whilst once first-line treatment for hypertension, their role was downgraded in June 2006 in the United Kingdom to fourth-line as they perform less well than other drugs, particularly in the elderly, and there is increasing evidence that the most frequently used beta-blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes. Hypertension вЂў http://www.healthscout.com/animation/6 8/47/main.html What are пЃў-blockers used for? вЂў Numerous studies suggest that beta-blockers can reduce mortality by 25% to 40% in patients with certain kinds of heart failure, and cut sudden cardiac death up to 50% in patients with a recent heart attack. вЂў Current Uses вЂў TreatmentпЅҐAngina pectoris (chest pain associated with lack of oxygen to the heart)пЅҐArrhythmias (irregular heart rhythms)пЅҐHeart attackпЅҐHeart failureпЅҐHypertension (high blood pressure) вЂў PreventionпЅҐProtects the heart in people who have coronary artery diseaseпЅҐReduces risk of strokeпЅҐ Protective prior to non-cardiac surgery in persons at high risk of complications Heart Failure вЂў http://www.healthscout.com/animation/6 8/13/main.html вЂў http://www.medindia.net/animation/heart _attack.asp How do пЃў-blockers work? вЂў вЂў вЂў Mechanism for How It WorksпЅҐBeta-blockers "block" the effects of adrenaline on your body's beta-receptors. This slows the nerve impulses that travel through the heart. As a result, your heart does not have to work as hard because it needs less blood and oxygen. This decreases heart rate, blood pressure, and lessens the need for nitrates. Beta-blockers also block the impulses that can cause an arrhythmia (abnormal heart beat).пЅҐ Beta-blockers generally work by affecting the response to some nerve impulses. Your body has 2 main beta-receptors: beta 1 and beta 2. Some beta-blockers are selective, which means that they block beta 1 receptors more than they block beta 2 receptors. Beta 1 receptors are responsible for heart rate and the strength of your heartbeat. Nonselective beta-blockers block both beta 1 and beta 2 receptors. Beta 2 receptors are responsible for the function of your smooth muscles (muscles that control body functions but that you do not have control over).пЅҐ This class of drugs may decrease the sympathetic outflow from the central nervous system and/or suppress the release of reninпѕ‘a substance that is elevated in some patients with high blood pressure and is involved in a cascade of events leading to constriction of blood vessels. In addition, some speculate that beta-blockers may have possible antioxidant and cholesterol lowering effects. Strategy for design of пЃў-blockers вЂў Begin design by identifying a molecule selective for пЃў-receptors вЂў For example, we discussed the following molecule, which is a reasonably selective пЃўagonist (e.g. isoprenaline) OH HO H N HO Iso pren aline Design of пЃў-blockers вЂў Remove phenolic OH groups, which are necessary for пЃў-agonism OH Cl H N Cl D ichloroisoprenaline (now a partial agonist) пЃў-blocker design вЂў Replace two chlorine atoms with a fused aryl ring вЂў Resulted in a partial agonist, which partially blocked effect of epinephrine OH H N P ronethalol (still a partial agonist) пЃў-blocker design вЂў Next extend the side chain to try and achieve вЂњumbrellaвЂќ effect вЂў Serendipity comes into play, as one synthetic intermediate is not available in the research lab, another is used, and a drug is discovered. OH O H N OH O T arg et S tru cture H N P ro pran o lol пЃў-blocker design вЂў Propranolol (INN) (IPA: [proЛ€prпЅѕnЙ™loКЉl]) is a nonselective beta blocker mainly used in the treatment of hypertension. It was the first successful beta blocker developed. Propranolol is commonly marketed by AstraZeneca under the trade name Inderal. вЂў Scottish scientist James W. Black successfully developed propranolol in the late 1950s. He was awarded the Nobel Prize in Medicine for this discovery in 1988. Examples of beta blockers Dichloroisoprenaline, the first beta blocker. Alprenolol Carteolol Levobunolol Mepindolol Metipranolol Nadolol Oxprenolol Penbutolol Pindolol Propranolol Sotalol Timolol ОІ1-Selective agents Acebutolol Atenolol Betaxolol Bisoprolol Esmolol Metoprolol Nebivolol Mixed О±1/ОІ-adrenergic antagonists Carvedilol Celiprolol Labetalolprolol LabetalolпїЅпїЅпїЅ пїЅпїЅпїЅпїЅпїЅпїЅпїЅпїЅпїЅпїЅпїЅпїЅпїЅиЂЂиЂЂОЊж±ЈжҐЇпїЅаґ« Some пЃў-blockers are also used to treat glaucoma http://www.goodhope.org.uk/departments/eyedept/images/gl aucoma.html http://www.goodhope.org.uk/departments/eyedept/angleclosu reetc.htm http://www.goodhope.org.uk/departments/eyedept/dropsfor.h tm Non-specific пЃў-blockers (antagonize both пЃў1 and пЃў2 receptors) OH OH H N O OH OH H N O H N H N O O O N H O C arteo lo l P ro p rano lo l OH OH OH H N O M etip rano lo l (O p tiP rano lo l, G lauco m a) L ev ob un olo l O O O H N H N OH H N HO M eSO 2 N H N H HO N ado lo l (C o rg ard , b lo od pressu re, ch est p ain ) O x p ren olol P ind olo l OH H N O O N N N S T im olol (oral form is B lo cadren ) (O pth alm ic fo rm T im op to l or T im o p tic) S o talol (also in h ib its in w ard p o tassium ch an n els in the h eart) Selective (пЃў1 selective) пЃў-blockers H N O H N O H N O OH OH OH OH OH H N O H N O O O NH2 HN O O O O A cebutolol A tenolol B etaxolol (B etoptic, L okren) E sm olol (B revibloc) M etoprolol (L opressor, N ovartis) (also T oprol-X L , B etaloc (A straZ eneca) Why do you want selective antagonists? вЂў Acebutolol is a cardioselective beta blocker. It is more suitable than non cardioselective beta blockers, if a patient with Asthma bronchiale or chronic obstructive lung disease (COLD) needs treatment with a beta blocker. Non-selective пЃў-blockers which also antagonize at the пЃЎ1 receptor M eO OH O H N OH O N H C arv ed ilo l (C oreg , G S K ) (D ilatren d, E u cardic, R o ch e) H N HO O NH2 L ab etalo l (N orm o d yn e, T ran d ate) Why add пЃЎ1 antagonism? вЂў In addition to blocking both ОІ1- and ОІ2adrenergic receptors, carvedilol also displays О±1-adrenergic antagonism, which confers the added benefit of reducing blood pressure through vasodilation. Biosynthesis of norepinephrine and epinephrine NH2 C O 2H HO HO T y ro sin e hyd ro x y lase NH2 C O 2H HO L -T y ro sine HO D o pa D ecarb o xy lase NH2 HO D o pam ine L ev od op a OH OH D o p am in e пЃў -h yd rox y lase HO HO NH2 N -m eth y l transferase (in A d ren al m ed ulla) HO N orep in ep hrin e (N oradren aline) NHMe HO E pinep hrine (A d renalin e) A competitive inhibitor of tyrosine hydroxylase can be used to slow production of catecholamines NH2 C O 2H HO пЃЎ -M ethyltyrosine Inhibition of catecholamine synthesis п‚• пЃЎ-methyltyrosine is occasionally used to treat hypertension associated with tumors in the adrenal medulla Reserpine вЂў Reserpine was isolated in 1952 from the dried root of Rauwolfia serpentina (Indian snakeroot), and introduced in 1954, two years after chlorpromazine. Reserpine almost irreversibly blocks the uptake (and storage) of noradrenaline and dopamine into synaptic vesicles by inhibiting the Vesicular Monoamine Transporters (VMAT). In so doing, it leaves the noradrenaline in the cytoplasm, where it is destroyed by monamine oxidase (MAO). It was once used to treat hypertension, but has many side effects, including depression, stomach cramps, diarrhea, etc. OCH 3 H N O OCH3 O C H 3O N H OCH3 H H C H 3O 2C OCH3 Norepinephrine Reuptake Inhibitors as Antidepressants вЂў Norepinephrine reuptake inhibitors (NRIs), also known as noradrenaline reuptake inhibitors (NARIs), are compounds that elevate the extracellular level of the neurotransmitter norepinephrine in the central nervous system by inhibiting its reuptake from the synaptic cleft into the presynaptic neuronal terminal. The drugs inhibit the class of neurotransmitter transporters known as norepinephrine transporters. They have virtually no action at other monoamine transporters. Depression вЂў http://www.healthcentral.com/depressio n/introduction-5003-109.html вЂў http://www.healthcentral.com/depressio n/introduction-5003-109.html вЂў http://www.healthscout.com/animation/6 8/10/main.html What is serotonin? NH2 HO 5 -H yd ro xytryp ta m in e , o r 5 -H T N H In the central nervous system, serotonin is believed to play an important role in the regulation of body temperature, mood, sleep, vomiting, sexuality, and appetite. Low levels of serotonin have been associated with several disorders, namely clinical depression, obsessivecompulsive disorder (OCD), migraine, irritable bowel syndrome, tinnitus, fibromyalgia, bipolar disorder, and anxiety disorders. If neurons of the brainstem that make serotoninвЂ”serotonergic neuronsвЂ”are abnormal, there is a risk of sudden infant death syndrome (SIDS) in an infant. Understanding Serotonin вЂў The pharmacology of 5-HT is extremely complex, with its actions being mediated by a large and diverse range of 5-HT receptors. At least seven different receptor "families" are known to exist, each located in different parts of the body and triggering different responses. As with all neurotransmitters, the effects of 5-HT on the human mood and state of mind, and its role in consciousness, are very difficult to ascertain. Understanding Serotonin вЂў Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, 5-HT reuptake transporter, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), cocaine, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).Recent research suggests that serotonin plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout the body. Norepinephrin Reuptake Inhibitors for Depression H 3C OH O HO CH3 NHCH3 N H HO A to m o xetine (S trattera, E li L illy & C o .) E pinep h rin e вЂў Atomoxetine is classified as a norepinephrine reuptake inhibitor, and is approved for use in children, adolescents, and adults. вЂў Atomoxetine is the first non-stimulant drug approved for the treatment of attention-deficit hyperactivity disorder (ADHD). It is sold in the form of the hydrochloride salt of atomoxetine. It is manufactured and marketed under the brand name StratteraпЅЁ by Eli Lilly and Company as a generic Attentin by Torrent Pharmaceuticals. There is currently no generic available within the United States due to patent restrictions.